Frits van Rhee, MD, PhD, professor, director, Myeloma Center, University of Arkansas for Medical Sciences, Charles and Clydene Scharlau Chair for Hematological Malignancies, discusses the clinical implications of CAR T-cell therapy for patients with relapsed/refractory multiple myeloma.

Currently, CAR T-cell therapy is approved for patients who have received more than 4 prior lines of therapy and who have progressed on treatment with a proteasome inhibitor, as well as an anti-CD38 monoclonal antibody, according to van Rhee. Most patients who are currently receiving CAR T-cell therapy are those with advanced disease. The treatment is a very important option for those who are difficult to treat, and who have historically poor outcomes, van Rhee adds. 

The MAMMOTH trial, which was a retrospective analysis of 275 patients, demonstrated that patients with refractory disease have a short overall survival, varying from 5 to 11 months, depending on how many agents they are refractory to, van Rhee explains. As such, there is a need for improved treatments for those with relapsed/refractory disease, and CAR T-cell therapy offers hope for this patient population, van Rhee concludes.

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Frits van Rhee, MD, PhD, discusses the clinical implications of CAR T-cell therapy for patients with relapsed/refractory multiple myeloma.

Dr. Van Rhee on the Clinical Implications of CAR T-Cell Therapy in Relapsed/Refractory Myeloma 

Frits van Rhee, MD, PhD, professor and director of the myeloma center at the University of Arkansas for Medical Sciences, and Charles and Clydene Scharlau Chair for Hematological Malignancies, discusses future research directions with CAR T-cell therapy for the treatment of patients with multiple myeloma. 

A significant question that remains with CAR T-cell therapy in for patients with multiple myeloma is where it fits into the treatment algorithm, according to van Rhee. It is feasible that this therapy could be given early in the course of treatment, such as for patients who experience early relapse, those who are diagnosed with aggressive disease, or as a replacement for stem cell transplantation, van Rhee says. 

Another future opportunity with this modality is to improve upon existing CAR T-cell therapies, van Rhee adds. Thus far, CAR T-cell therapy has been exciting due to the results obtained with only first-generation products, van Rhee notes. To build on this, it is important to examine how to make these treatments persist, and last longer in patients, as well as understand how the bone marrow microenvironment affects the efficacy of these treatments, van Rhee concludes.

Frits van Rhee, MD, PhD, discusses future research directions with CAR T-cell therapy for the treatment of patients with multiple myeloma.

Dr. Van Rhee on Future Research Directions for CAR T-Cell Therapy in Multiple Myeloma 

Multiple myeloma (MM) IS generally considered an incurable malignancy, although a proportion of patients may achieve long-term disease-free survival with a comprehensive and aggressive treatment approach.

 The therapeutic armamentarium has rapidly expanded in recent years because of the approval of novel drugs such as carfilzomib (Kyprolis), ixazomib (Ninlaro), pomalidomide, daratumumab (Darzalex), and selinexor (Xpovio). Others, such as melflufen, likely will come to market in the near future. These drugs have especially improved the treatment options for relapsed disease, with some agents now also being used as frontline therapy. As a result, outcomes for patients with newly diagnosed and relapsed disease continue to improve with prolongation of median survival to greater than 7 years from diagnosis.

Immunotherapy holds great promise for the treatment of MM following the trends seen with developments in the lymphoma field. The addition of the anti-CD20 monoclonal antibody rituximab (Rituxan) to cyclophosphamide, doxorubicin hydrochloride (Adriamycin), vincristine sulfate (Oncovin), and prednisone has greatly improved the prognosis of lymphoma. Additionally, the antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris) has had a similar impact on Hodgkin lymphoma. Innovative immunotherapeutics also are finding their way into the MM field and are set to have a transformative effect on the prognosis of both patients with transplant-eligible and ineligible MM with the possibility of the elusive goal of cure within the reach of many more patients in the not-too-distant future.

Immunotherapy for MM comprises exciting new agents, such as chimeric antigen receptor (CAR) T cells, “naked” antibodies, bispecific antibodies, ADCs, vaccines and new immunomodulatory agents such as the cereblon E3 ligase modulators (CELMoDs). Herein, the focus will be on the development of monoclonal antibody therapeutics.

The anti-CD38 monoclonal antibody daratumumab is approved as frontline therapy for patients with MM who are eligible based on data from the phase 3 Cassiopeia trial (NCT02541383). Investigators evaluated daratumumab (D) in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus VTd alone. Patients treated with D-VTd (n = 543) achieved a more frequent stringently defined complete remission compared with those treated with VTd (n = 542) at rates of 39% versus 26%, respectively. Patients also had higher rates of minimal residual disease negativity (64% vs 44%, respectively).

In the GRIFFIN study (NCT02874742), investigators evaluated daratumumab with the lenalidomide, bortezomib, dexamethasone backbone (RVd) as induction and consolidation therapy in patients who were candidates for high-dose therapy with melphalan followed by stem cell transplantation. Overall, patients treated with D-RVd achieved a more frequently stringent complete response compared with those receiving standard RVd (62.6% vs 45.4%, respectively). Patients with standard cytogenetic risk (n = 79) were the principal beneficiaries of therapy with daratumumab (stringent complete response, 49.4%; OR, 2.03; 95% CI, 1.05-3.85).

Data from the ongoing phase 3 PERSEUS registration study (NCT03710603) will determine whether subcutaneous formulation of daratumumab and hyaluronidase human-fihj (Darzalex Faspro) in combination with RVd improves progression-free survival (PFS) in patients with transplant-eligible newly diagnosed MM. It seems likely that the quadruplet regimens of D-RVd and D-VTd will become the new standards of care as upfront therapy in MM. Daratumumab is approved for nontransplant-eligible disease in combination with lenalidomide and dexamethasone; bortezomib, melphalan, and prednisone; as well in the relapse setting in combination with bortezomib, lenalidomide, or pomalidomide.

A second anti-CD38 monoclonal antibody, isatuximab-irfc (Sarclisa), which has a somewhat different mechanism of action and recognizes a different epitope, was approved in 2020 for patients with relapsed/refractory MM based on data from the ICARIA-MM study (NCT02990338). Patients treated with isatuximab, pomalidomide, and dexamethasone had superior PFS compared with those who received pomalidomide and dexamethasone (11.5 vs 6.5 months, respectively).

Elotuzumab (Empliciti) is a monoclonal antibody recognizing the cell surface glycoprotein SLAMF7 or CS1 that was approved for relapsed/refractory MM in combination with lenalidomide and dexamethasone.10 Data from the randomized phase 3 ELOQUENT-3 study (NCT02654132) showed that elotuzumab performed particularly well in combination with pomalidomide and dexamethasone (EPd). Patients in the EPd arm (n = 60) had significantly higher overall response rates (53% vs 26%) and prolonged PFS (10.3 vs 4.7 months) compared with those who received Pd alone (n = 57).

A common theme of this class of antibodies is that these agents are generally well tolerated with manageable toxicities, are easily combined with existing agents, and can be given to elderly patients. It is also important to note that monoclonal antibodies such as daratumumab are used as an adjunct to melphalan-based stem cell transplantation in newly diagnosed patients. Future studies are needed to clarify whether these novel combinations can safely permit delayed transplantation or even avoid transplantation altogether.

A large number of bispecific antibodies are in clinical development for relapsed/ refractory MM.12 Bispecific T-cell engagers (BiTEs) have dual antigen specificity. BiTEs bind to and activate T cells via the CD3/Tcell receptor complex and link activated immune T effectors to MM cells by binding to a MM-associated tumor antigen. In comparison with CAR T cells, bispecific antibodies have advantages such as off-the-shelf use (which eliminates the need for a cellular manufacturing), immediate availability of the drug, and lack of need for lymphodepleting chemotherapy.

A disadvantage of bispecific antibodies is that they are ill-suited for heavily treated patients since their activity is critically dependent on the fitness of the patient’s immune cells. In addition, the short half-life requires continuous infusion and has been an issue in some studies. As with CAR T cells, bispecific antibodies can have significant adverse effects, including cytokine release syndrome and neurotoxicity. Most bispecific antibodies are directed at B-cell maturation antigen (BCMA); however, other targets are under investigation, including CD56, CD38, Fc receptor-like protein 5 (FCRL5), and G-protein coupled receptor family C group 5-member D (GPRC5D).

Data from a phase 1 clinical trial (NCT02514239) investigating the BiTE molecule AMG 420 that targets BCMA showed a response rate of 70% at the maximum-tolerated dose of 400 mg/day with 5 of 10 patients achieving a stringently defined complete response.

 Investigators are evaluating AMG 701, a BiTE molecule modified to have a longer half-life, in a successor clinical trial (NCT03287908).

ADCs are monoclonal antibodies that target a cytotoxic cargo to MM cells. Upon binding to the target antigen, the ADC complex is internalized, and then the cytotoxic molecule is released. The ADC class of monoclonal antibodies is attractive because the agents can be safely used in patients with a high disease burden without the risk of cytokine release syndrome or neurotoxicity. Belantamab mafodotin-blmf (Blenrep) is an ADC that targets BCMA and is conjugated to the microtubule poison monomethyl auristatin F. The agent was recently approved for relapsed/ refractory MM based on data from the DREAMM-2 study (NCT03525678) in which it demonstrated responses in patients who had received a median of 7 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Corneal keratopathy was the principal adverse effect observed. Belantamab mafodotin is administered under a risk evaluation and mitigation strategy program. Studies of the agent in combination with MM backbone drugs are ongoing.

Monoclonal antibodies have made a significant impact on the treatment landscape of MM. Current and future studies will define how best to incorporate these agents into the developing treatment stratagems for patients with both newly diagnosed and relapsed MM.

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Articles

Novel drugs have especially improved the treatment options for relapsed myeloma, with some agents now also being used as frontline therapy. As a result, outcomes for patients with newly diagnosed and relapsed disease continue to improve with prolongation of median survival to greater than 7 years from diagnosis.

Frits Van Rhee, MD, PhD

Articles

Dr. Van Rhee on the Clinical Implications of CAR T-Cell Therapy in Relapsed/Refractory Myeloma

Dr. Van Rhee on Future Research Directions for CAR T-Cell Therapy in Multiple Myeloma

Monoclonal Antibodies Prove to Be Novel Therapeutics for Myeloma